Avatrombopag (Monograph)

Brand name: Doptelet
Drug class: Hematopoietic Agents
Chemical name: 1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid
Molecular formula: C₂₉H₃₄Cl₂N₆O₃S₂•C₄H₄O₄
CAS number: 677007-74-8

Medically reviewed by Drugs.com on Feb 18, 2025. Written by ASHP.

Introduction

Small-molecule thrombopoietin receptor agonist (TPO-RA).

Uses for Avatrombopag

Thrombocytopenia in Chronic Liver Disease

Treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.

Follow recommended dosage guidelines to achieve target platelet counts to minimize risk of bleeding; do not use to normalize platelet counts.

Immune Thrombocytopenia

Treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP; also known as idiopathic thrombocytopenic purpura) who have had an insufficient response to a prior treatment (designated an orphan drug by FDA for use in this condition).

Follow recommended dosage guidelines to achieve and maintain platelet counts ≥50,000/mm³ as necessary to reduce the risk of bleeding; do not use to normalize platelet counts.

Thrombopoietin receptor agonists (TPO-RAs) are used as second-line therapy for treatment of ITP, generally following lack of platelet response with corticosteroids and/or IV immune globulin (IVIG). Corticosteroids remain the standard initial therapy for newly diagnosed patients with ITP, but should be used for a limited duration only because of adverse effects. Individualize treatment decisions and consider comparative risks and benefits, and adverse effects of therapy.

Avatrombopag Dosage and Administration

General

Patient Monitoring

When used in patients with chronic liver disease undergoing a procedure, obtain a platelet count prior to administration of the drug and on the day of the procedure to ensure an adequate increase in platelet count.
When used in patients with immune thrombocytopenia (ITP), assess platelet counts weekly until a stable platelet count ≥50,000/mm³ has been achieved, and then obtain platelet counts monthly thereafter. Obtain platelet counts weekly for at least 4 weeks following discontinuance of therapy.

Administration

Oral Administration

Administer orally once daily with food.

Dosage

Available as avatrombopag maleate; dosage expressed in terms of avatrombopag.

Adults

Thrombocytopenia in Chronic Liver Disease

Patients Scheduled to Undergo a Procedure

Oral

Administer once daily for 5 days, starting 10–13 days prior to the scheduled procedure; patients should undergo the procedure 5–8 days after the last dose of the drug is administered.

Recommended dosage is based on patient's platelet count prior to the procedure.

Platelet count <40,000/mm³: 60 mg once daily for 5 days.

Platelet count 40,000 to <50,000/mm³: 40 mg once daily for 5 days.

If a dose is missed, take the dose as soon as it is remembered. Do not take double dose to make up for a missed dose. All 5 days of dosing should be completed.

Chronic Immune Thrombocytopenia

Oral

Initially, 20 mg once daily. In patients receiving concomitant therapy with a moderate or potent dual inhibitor of CYP2C9 and CYP3A4, reduce initial dosage of avatrombopag to 20 mg 3 times a week. In patients receiving concomitant therapy with a moderate or potent dual inducer of CYP2C9 and CYP3A4, increase initial dosage of avatrombopag to 40 mg once daily.

Adjust dosage based on platelet count response (see Table 1). Use the lowest effective dosage to achieve and maintain platelet count ≥50,000/mm³ as necessary to reduce the risk of bleeding. Do not use avatrombopag to normalize platelet counts.

Assess platelet count weekly until a stable platelet count ≥50,000/mm³ has been achieved; assess platelet count monthly thereafter.

Table 1. Dosage Adjustment for Avatrombopag Based on Platelet Count in Patients with Chronic ITP1
Platelet Count	Dosage Adjustment
<50,000/mm³ after at least 2 weeks of avatrombopag therapy	Increase dosage by 1 dose level (see Table 2); wait 2 weeks to assess the effects of this and any subsequent dosage adjustments
200,000–400,000/mm³	Decrease dosage by 1 dose level (see Table 2); wait 2 weeks to assess the effects of this and any subsequent dosage adjustments
>400,000/mm³	Interrupt therapy and monitor platelet count twice weekly; once platelet count <150,000/mm³, restart at a dosage reduced by 1 dose level (see Table 2)
<50,000/mm³ after 4 weeks of therapy with avatrombopag 40 mg daily (highest recommended dosage)	Discontinue therapy
>400,000/mm³ after 2 weeks of therapy with avatrombopag 20 mg weekly (lowest recommended dosage)	Discontinue therapy

Table 2. Avatrombopag Dose Levels for Titration in Patients with Chronic ITP1
Dosage	Dose Level
40 mg once daily (highest recommended dosage)	6
40 mg 3 times a week and 20 mg on the 4 remaining days of each week	5
20 mg once daily (usual initial recommended dosage)	4
20 mg 3 times a week	3
20 mg twice a week or 40 mg once weekly	2
20 mg once weekly (lowest recommended dosage)	1

If a dose is missed, take the dose as soon as it is remembered. Do not take double dose to make up for a missed dose.

If a moderate or potent dual inhibitor or inducer of CYP2C9 and CYP3A4 is initiated in a patient receiving chronic avatrombopag therapy, adjust the dosage of avatrombopag based on platelet count monitoring.

Following discontinuance of therapy, assess platelet counts weekly for at least 4 weeks.

Prescribing Limits

Adults

Chronic Immune Thrombocytopenia

Oral

Do not exceed a dosage of 40 mg daily.

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with chronic liver disease.

Cautions for Avatrombopag

Contraindications

None.

Warnings/Precautions

Thrombotic/Thromboembolic Complications

Thrombopoietin receptor agonists (TPO-RAs) have been associated with thrombotic and thromboembolic complications.

Consider potential increased risks of thrombotic and thromboembolic complications in patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (e.g., factor V Leiden, prothrombin 20210A, antithrombin deficiency, protein C or S deficiency).

Follow recommended dosage guidelines to achieve target platelet counts. Do not attempt to normalize platelet counts.

Monitor platelet count during and after avatrombopag therapy; in addition, monitor patients for signs and symptoms of thromboembolic events. If thromboembolic events occur, promptly institute appropriate treatment.

Specific Populations

Pregnancy

May cause fetal harm based on animal findings. No adequate data in humans; in animal studies, adverse developmental outcomes observed at dose exposures substantially higher than those achieved with the maximum human dosage.

Apprise pregnant women of fetal risk.

Lactation

Distributed into milk in rats; not known whether the drug is distributed into human milk. Effects on milk production or on breast-fed infant also not known.

Advise women not to breast-feed during therapy and for at least 2 weeks after the last dose is administered. If the drug is used for brief periods (i.e., prior to a procedure in patients with chronic liver disease) in a lactating woman, manufacturer recommends that breast-feeding be interrupted and affected milk discarded during treatment and for 2 weeks after the last dose is administered.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. No clinically important differences in response observed.

Hepatic Impairment

Pharmacokinetics not substantially altered in patients with hepatic impairment (Child-Pugh class A, B, or C, or Model for End-Stage Liver Disease [MELD] score 4–23).

Renal Impairment

Pharmacokinetics not substantially altered in patients with mild or moderate renal impairment (Cl_cr ≥30 mL/minute).

Pharmacokinetics not established in patients with severe renal impairment, including those requiring dialysis.

Pharmacogenomic Considerations

Slightly higher avatrombopag exposures observed in intermediate or poor CYP2C9 metabolizers compared with CYP2C9 extensive metabolizers; not considered clinically important.

The manufacturer makes no specific dosage recommendations based on CYP2C9 metabolizer genotype.

Common Adverse Effects

Patients with chronic liver disease (≥3%): Pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

Patients with chronic ITP (≥10%): Headache, fatigue, contusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae, and nasopharyngitis.

Drug Interactions

Metabolized by CYP2C9 and CYP3A4. Weak inducer of CYP2C8 and CYP2C9 in vitro but does not induce CYP isoenzymes 1A, 2B6, 2C, or 3A or inhibit CYP isoenzymes 1A, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A in vitro.

In vitro, inhibits breast cancer resistance protein (BCRP) and organic anion transporter (OAT) 3, but does not inhibit organic anion transporting polypeptide (OATP) 1B or 1B3, organic cation transporter (OCT) 2, or OAT1.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Clinically important pharmacokinetic interaction not expected; dosage adjustments not necessary.

Dual CYP2C9 and CYP3A4 inhibitors: Moderate or potent dual inhibitors of CYP2C9 and CYP3A4 may result in increased avatrombopag exposure and increased risk of toxicity. If chronic avatrombopag therapy (i.e., for the treatment of chronic ITP) is initiated in a patient receiving a moderate or potent dual inhibitor of CYP2C9 and CYP3A4, reduce the starting dosage of avatrombopag to 20 mg 3 times a week. If a moderate or potent dual inhibitor of CYP2C9 and CYP3A4 is initiated in a patient already receiving chronic avatrombopag therapy, adjust the dosage of avatrombopag based on platelet count monitoring.

Dual CYP2C9 and CYP3A4 inducers: Moderate or potent dual inducers of CYP2C9 and CYP3A4 may result in decreased avatrombopag exposure and reduced efficacy. If chronic avatrombopag therapy (i.e., for the treatment of chronic ITP) is initiated in a patient receiving a moderate or potent dual inducer of CYP2C9 and CYP3A4, increase the starting dosage of avatrombopag to 40 mg once daily. If a moderate or potent dual inducer of CYP2C9 and CYP3A4 is initiated in a patient already receiving chronic avatrombopag therapy, adjust the dosage of avatrombopag based on platelet count monitoring.

Drugs Affecting P-glycoprotein Transport

P-gp inhibitors: Clinically important pharmacokinetic interaction not expected.

Specific Drugs

Drug	Interaction	Comments
Antifungal agents (fluconazole, itraconazole)	Fluconazole (dual CYP2C9 and CYP3A4 inhibitor): Increased peak plasma concentration and AUC of avatrombopag ; substantially higher maximum platelet count Itraconazole (potent CYP3A inhibitor): slightly increased peak plasma concentration and AUC of avatrombopag; not considered clinically important	Fluconazole: If chronic avatrombopag therapy (e.g., for the treatment of chronic ITP) is initiated in a patient receiving fluconazole, reduce starting dosage of avatrombopag to 20 mg 3 times a week If fluconazole is initiated in a patient receiving chronic avatrombopag therapy, adjust avatrombopag dosage based on platelet count monitoring Itraconazole: Dosage adjustment not necessary
Cyclosporine	In healthy individuals, mild effects on avatrombopag exposure observed; not expected to be clinically important
Rifampin	Decreased avatrombopag AUC; platelet counts returned to baseline within 7 days compared with 27 days when avatrombopag was administered without concomitant rifampin	If chronic avatrombopag therapy (e.g., for the treatment of chronic ITP) is initiated in a patient receiving rifampin, increase the starting dosage of avatrombopag to 40 mg once daily If rifampin is initiated in a patient receiving chronic avatrombopag therapy, adjust the dosage of avatrombopag based on platelet count monitoring
Verapamil	In healthy individuals, mild effects on avatrombopag exposure observed; not expected to be clinically important

Avatrombopag Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are dose-proportional over dose range of 10–80 mg.

Following oral administration, peak plasma avatrombopag concentrations occur at 5–6 hours.

Onset

Platelet count increases observed within 3–5 days after treatment initiation and peak after 10–13 days.

Food

Low- or high-fat meal delays time to peak plasma concentration by 0–2 hours but does not affect peak plasma concentration or AUC.

Food reduces variability of drug exposure by 40–60%.

Special Populations

Pharmacokinetics are similar between healthy individuals and patients with chronic liver disease.

Pharmacokinetics not substantially altered in patients with hepatic impairment (Child-Pugh score A, B, or C, or Model for End-Stage Liver Disease [MELD] score 4–23).

Pharmacokinetics not substantially altered in patients with mild or moderate renal impairment (Cl_cr ≥30 mL/minute).

In poor or intermediate CYP2C9 metabolizers (i.e., patients with CYP2C9*2 or *3 polymorphism), systemic exposure is approximately 1.4-fold or 2-fold higher, respectively, compared with CYP2C9 extensive metabolizers.

Distribution

Plasma Protein Binding

>96%.

Elimination

Metabolism

Metabolized principally by CYP2C9 and CYP3A4.

Elimination Route

Excreted in feces (88%) and urine (6%). Unchanged drug excreted in feces accounts for 34% of the dose.

Hemodialysis not expected to affect elimination.

Half-life

Approximately 19 hours.

Stability

Storage

Oral

Tablets

Store at 20–25°C (excursions permitted to 15–30°C). Store in original package.

Actions

Interacts with the transmembrane domain of the thrombopoietin (TPO) receptor and stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets.
Exhibits additive effects with TPO on platelet production; does not inhibit TPO binding to the receptor.
Increases platelet counts in a dose- and exposure-dependent manner.
Platelet count increases observed within 3–5 days and peak after 10–13 days. Following short-term therapy in patients with chronic liver disease undergoing a scheduled procedure, platelet counts decreased 7 days after the procedure and returned to near baseline values within 35 days.

Advice to Patients

Importance of instructing patients or caregivers to read the manufacturer’s patient information.
Risk of thrombotic or thromboembolic complications. Importance of patients immediately informing their clinician if signs and symptoms of a blood clot (e.g., swelling, pain, or tenderness in the leg, tachycardia, shortness of breath, abdominal pain or tenderness, or chest pain) occur.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of advising women to avoid breast-feeding while receiving the drug and for 2 weeks after the last dose is administered.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.